Abrol Ravinder, Griffith Adam R, Bray Jenelle K, Goddard William A
Materials and Process Simulation Center, MC, California Institute of Technology, Pasadena, CA, USA.
Methods Mol Biol. 2012;914:237-54. doi: 10.1007/978-1-62703-023-6_14.
G protein-coupled receptors (GPCRs) are integral membrane proteins whose "pleiotropic" nature enables transmembrane (TM) signal transduction, amplification, and diversification via G protein-coupled and β arrestin-coupled pathways. GPCRs appear to enable this by being structurally flexible and by existing in different conformational states with potentially different signaling and functional consequences. We describe a method for the prediction of the three-dimensional structures of these different conformations of GPCRs starting from their amino acid sequence. It combines a unique protocol of computational methods that first predict the TM regions of these receptors and TM helix shapes based on those regions, which is followed by a locally complete sampling of TM helix packings and their scoring that results in a few (~10-20) lowest energy conformations likely to play a role in binding to different ligands and signaling events. Prediction of the structures for multiple conformations of a GPCR is starting to enable the testing of multiple hypotheses related to GPCR activation and binding to ligands with different signaling profiles.
G蛋白偶联受体（GPCRs）是整合膜蛋白，其“多效性”性质能够通过G蛋白偶联途径和β抑制蛋白偶联途径实现跨膜（TM）信号转导、放大和多样化。GPCRs似乎通过结构灵活性以及以具有潜在不同信号传导和功能后果的不同构象状态存在来实现这一点。我们描述了一种从GPCRs的氨基酸序列预测其不同构象三维结构的方法。它结合了一种独特的计算方法协议，该协议首先基于这些区域预测这些受体的TM区域和TM螺旋形状，随后对TM螺旋堆积进行局部完全采样并对其进行评分，从而产生一些（约10 - 20个）可能在与不同配体结合和信号传导事件中起作用的最低能量构象。对GPCR多种构象结构的预测开始能够测试与GPCR激活以及与具有不同信号特征的配体结合相关的多种假设。
